TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a.
TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a.
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DOI：
10.1093/nar/gkx064
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发表时间：
2017-03-17
影响因子：
14.9
通讯作者：
Kishimoto T
中科院分区：
文献类型：
--
作者：
Nyati KK;Masuda K;Zaman MM;Dubey PK;Millrine D;Chalise JP;Higa M;Li S;Standley DM;Saito K;Hanieh H;Kishimoto T
富含AT的相互作用结构域蛋白5a（Arid 5a）通过调节白细胞介素-6（IL-6）mRNA的半衰期在自身免疫中起关键作用。然而，Arid 5a介导的IL-6 mRNA稳定性调节的信号转导途径在很大程度上是未知的。在此，我们发现在脂多糖（LPS）刺激的早期阶段，NF-κB和NF-κ B触发的IL-6正反馈环激活Arid 5a基因表达，通过稳定IL-6 mRNA增加IL-6表达。随后，促分裂原活化蛋白激酶（MAPK）磷酸酶-1（MKP-1）促进富含AU的元件RNA结合蛋白1（AUF-1）从细胞核易位至细胞质，在细胞质中，其通过结合至3个UTR中的富含AU的元件而使Arid 5a mRNA不稳定。这导致IL-6 mRNA表达下调。在LPS刺激的晚期，p38 MAPK磷酸化Arid 5a并将含有E3泛素蛋白连接酶1（WWP 1）的WW结构域募集到其复合物中，其进而以K48连接的方式泛素化Arid 5a，导致其降解。抑制Arid 5a磷酸化和降解增加IL-6 mRNA的产生。因此，我们的数据表明，LPS诱导的NF-κB和MAPK信号转导是控制IL-6 mRNA稳定分子Arid 5a调节所必需的。因此，这项研究大大增加了我们对IL-6调节机制的理解。
The AT-rich interactive domain-containing protein 5a (Arid5a) plays a critical role in autoimmunity by regulating the half-life of Interleukin-6 (IL-6) mRNA. However, the signaling pathways underlying Arid5a-mediated regulation of IL-6 mRNA stability are largely uncharacterized. Here, we found that during the early phase of lipopolysaccharide (LPS) stimulation, NF-κB and an NF-κB-triggered IL-6-positive feedback loop activate Arid5a gene expression, increasing IL-6 expression via stabilization of the IL-6 mRNA. Subsequently, mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) promotes translocation of AU-rich element RNA-binding protein 1 (AUF-1) from the nucleus to the cytoplasm, where it destabilizes Arid5a mRNA by binding to AU-rich elements in the 3΄ UTR. This results in downregulation of IL-6 mRNA expression. During the late phase of LPS stimulation, p38 MAPK phosphorylates Arid5a and recruits the WW domain containing E3 ubiquitin protein ligase 1 (WWP1) to its complex, which in turn ubiquitinates Arid5a in a K48-linked manner, leading to its degradation. Inhibition of Arid5a phosphorylation and degradation increases production of IL-6 mRNA. Thus, our data demonstrate that LPS-induced NF-κB and MAPK signaling are required to control the regulation of the IL-6 mRNA stabilizing molecule Arid5a. This study therefore substantially increases our understanding of the mechanisms by which IL-6 is regulated.